ABSTRACT Exercise training markedly improves multiple metabolic parameters, including improved insulin sensitivity and body composition. Exercise also has beneficial effects on the central nervous system (CNS), which in turn, regulates all peripheral tissues, including the liver, pancreas, skeletal muscle, heart and adipose tissue. Relatively little is known about the mechanisms underlying the changes in the CNS following exercise training that contribute to the beneficial effects of exercise. Our overarching hypothesis is that exercise induces several changes in hypothalamic neurons and neuroendocrine signals, which in turn regulate food intake, body composition, exercise endurance, and insulin sensitivity in key peripheral tissues. We will systematically explore how exercise training affects in vivo activity dynamics of SF1 neurons and their targets, and determine how modulation of SF1 neurons influences insulin sensitivity and metabolic adaptations to exercise. We will also test the hypothesis that exercise training induces changes in peripheral metabolic responses that are dependent on the release of glutamate from SF1 neurons onto pro-opiomelanocortin (POMC) neurons. These studies will rely on several unique mouse models that have been developed for these studies, and cutting edge techniques including in vivo neuronal imaging and optogenetics.